Autoimmune Disease of the Inner Ear Treatment & Management

The natural history of untreated immune-mediated inner ear disease is unknown; much of the current therapy is based on empiric clinical data gathered during the past few decades. A key feature of immune-mediated inner ear disease is a positive response to immunosuppressive therapy (ie, corticosteroids) in the form of improved hearing. ^[2]

• Consider aggressive treatment for every patient, assuming no contraindications to steroid therapy are present, including peptic ulcer disease, diabetes mellitus, glaucoma, hypertension, and history of tuberculosis. Short-term bursts of steroids usually are insufficient (except as an aid in diagnosis) and may result in relapse.

• No standardized regimens for corticosteroid therapy exist, yet many recommend a trial of high-dose prednisone (1 mg/kg/d) for 1 month, followed by a slow taper over several weeks to a maintenance dose of 10-20 mg/d or every other day. Occasionally, higher doses are needed to maintain hearing as disease activity waxes and wanes. Patients often learn what maintenance dose is sufficient, below which their hearing deteriorates.

• Not all patients respond to corticosteroid therapy in the same manner. Some show improvement in threshold, discrimination scores, or both. Others with fluctuation and progression before therapy stabilize without actually improving. Still others actually lose hearing despite immunosuppressive therapy.

• In some patients, hearing loss becomes refractory to steroids, or patients develop adverse effects of chronic steroid administration. These patients may be candidates for cytotoxic therapy.

• Overall steroid response rates are approximately 60%, defined as an improvement in threshold of 15 dB at 1 frequency, 10 dB at 2 consecutive frequencies, or a significant improvement in discrimination score.

• Cytotoxic drugs generally are used for steroid-intolerant patients or those who fail to demonstrate a continued response to steroid therapy. However, McCabe recommends cyclophosphamide in addition to steroids as a first-line treatment. ^[21]

• Cyclophosphamide is a cytotoxic drug with adverse effects, including myelosuppression, hemorrhagic cystitis, infertility, and increased risk of malignancy.

• Other cytotoxic agents are used to treat immune-mediated inner ear disease, including methotrexate and azathioprine (Imuran). Sismanis et al used low-dose methotrexate to treat a small group of patients with autoimmune SNHL. Significant improvement in speech discrimination, but not pure-tone averages, was observed. ^[22] A longitudinal, observational, descriptive study by Mata-Castro et al indicated that in patients with immune-mediated hearing loss, azathioprine can maintain hearing threshold and reduce the risk and slow the rate of relapse. In patients treated with azathioprine for 1 year, the investigators found no statistically significant change between pure-tone average at base line and after 1 year’s treatment, while the annual relative incidence rate of relapse was 0.52. ^[23]

• Harris et al performed, from 1998-2001 and across 10 tertiary care centers, a randomized, double-blind, placebo-controlled study of 67 patients with rapidly progressive, bilateral sensorineural hearing loss (SNHL). ^[24] Patients who had a response to a one-month prednisone challenge were randomized to receive either placebo or methotrexate (15-20 mg/wk). The authors found that methotrexate was not able to maintain the hearing improvements obtained by high-dose prednisone over time better than placebo. The authors mention, however, that patients may have benefitted from fewer hearing fluctuations over time, but this was not specifically measured by the study.

• Several recent studies studied etanercept (Enbrel) in the treatment of AIED. Etanercept is a potent tumor necrosis factor (TNF) antagonist often used in the treatment of rheumatoid arthritis. Cohen et al enrolled 20 patients in a 12-week blinded placebo-controlled randomized trial of etanercept (25 mg SC twice weekly) versus placebo. ^[25] They found that etanercept was no better than placebo for the treatment of AIED. Similarly, Harris et al found no benefit of methotrexate over placebo in a 12-month placebo-controlled randomized trial. Finally, Matteson et al studied 23 steroid-responsive patients who received etanercept, 25 mg twice weekly for 24 weeks in an open-label pilot study. ^[26] Although a significant improvement of hearing loss in these patients was not evident, the previously progressive hearing loss in 87% of these patients appeared to stabilize or improve. Of the patients with symptoms of vertigo, 50% noted improvement.

• A study by Pathak et al suggested that the antioxidant N-acetylcysteine (NAC) may be effective against AIED. The investigators found that peripheral blood mononuclear cells (PBMCs) in patients with AIED had higher baseline TNF-α and myeloperoxidase levels than did those of healthy controls. NAC, however, was found to discourage the lipopolysaccharide-mediated release of TNF- α from PBMCs while only minimally affecting the TNF-α pathway’s downstream targets. ^[27]

• In 1989, Luetje studied the use of plasmapheresis in patients with autoimmune inner ear disease. ^[28] Improvement in auditory function occurred in 6 of 8 patients, 3 of whom were able to discontinue immunosuppressive medication.

• Plasmapheresis involves filtering a patient's whole blood, which removes antibody, antigen, and immune complexes and other immune mediators. Albumin and normal saline are used as replacement fluids. The procedure is expensive and is considered an adjunctive therapy until further controlled studies determine its role in the treatment of immune-mediated inner ear disease.

Immune-mediated inner ear disease usually is bilateral and often responds to medical management. Surgery generally is not appropriate. However, intratympanic therapy performed under local anesthesia has been found to be beneficial for some patients with immune-mediated inner ear disease.

• Improvements in treatment may be facilitated by local delivery for both SNHL and autoimmune ear disease. Intratympanic administration of corticosteroids results in higher inner ear levels compared with systemic steroid administration. Intratympanic administration avoids the blood-labyrinthine barrier and systemic adverse effects observed with oral or intravenous steroids.

• Parnes et al used intratympanic steroids to treat 37 patients with a variety of inner ear disorders causing SNHL. ^[29] Patients with immune-mediated hearing loss showed promising results, as did several patients who presented with sudden SNHL.

• Steroids initially are administered through a myringotomy placed over the round window region. A tympanostomy tube is left in place for continued treatments.

• Otoendoscopy of the middle ear may be performed to confirm the location of the round window and identify any mucosal adhesions that may impede drug penetration.

• Silverstein developed a drug delivery system that involves placing a small wick through a tympanostomy tube directly into the round window niche. ^[30] This allows a patient to self-administer the medication into the ear canal, where the drug is absorbed by the wick and directly transported to the round window membrane.

• The different inner ear drug delivery methods can be summarized as follows:

  • Intratympanic drug delivery

    • Passive intratympanic delivery

    • Biodegradable polymer intratympanic delivery

    • Hydrogel-based intratympanic delivery

    • Nanoparticle delivery

    • Active intratympanic drug delivery

    • Round window microcatheter

    • Silverstein MicroWick

    • Preclinical Alzet osmotic pump

    • Other systems

  • Intracochlear drug delivery

    • Syringe delivery

    • Direct injection

    • Syringe pump delivery

    • Osmotic pump delivery

    • Cochlear prosthesis–based delivery

    • Other delivery devices

As treatment options improve for many inner ear diseases and injuries, methods for delivering precise and controlled doses become vital. Researchers in the field of inner ear drug delivery are constantly in the process of advancing new and existing techniques that support the arrival of better and better therapeutic compounds. Those suffering from hearing related disorders can look forward to improved quality of life as the field progresses. ^[31]

However, physicians must realize that a potential impact of glucocorticoids on ion homeostasis functions exists in addition to immune suppression. These functions are quite interlinked with regard to maintenance of the endolymphatic potential in fluids around auditory and vestibular hair cells. Therefore, assuming that all steroid-responsive hearing loss is due to immune processes simply cannot be justified in light of our current understanding of other cellular and molecular processes under the control of glucocorticoids. ^[32]

In a retrospective study of intratympanic dexamethasone for sudden sensorineural hearing loss after failure of systemic therapy, 39% of patients were found to recover 20 dB or 20% SDS (if treated within 6 weeks). This was higher than the figure of 9.1% in their controls. ^[33]

Cochlear implantation

A literature review by Lee et al indicated that in patients with primary or secondary AIED, hearing improvement can be achieved through cochlear implantation. Of 115 patients in the assessed reports, improvement was found in 114. Out of 85 patients for whom the necessary audiometric data were available to determine progress, 26 (30.6%) demonstrated improvement over the course of a few years, 28 patients (32.9%) maintained a “generally stable” hearing level over time, and 30 patients (35.3%) experienced improvement for up to a year before their progress plateaued or they suffered mild hearing reduction. In one patient (1.2%), pain led to complete deterioration after an initially good response. The investigators also reported that the risk of a poor response may be higher in persons with secondary AIED. ^[34]

Consultation with a rheumatologist or hematologist often is necessary if steroid therapy fails to help the patient and he or she requires treatment with cytotoxic drugs, which requires close hematologic monitoring. Occasionally, patients may require treatment with plasmapheresis (see Medical Care).

Patients with immune-mediated endolymphatic hydrops usually are placed on a low-sodium diet, similar to the diet recommended for patients with Ménière disease.